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首页> 外文学位 >Role du gene Polycomb BMI1 dans le maintien et la radioresistance des cellules souches cancereuses.
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Role du gene Polycomb BMI1 dans le maintien et la radioresistance des cellules souches cancereuses.

机译：Polycomb BMI1基因在癌症干细胞的维持和放射抵抗中的作用。

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摘要

Glioblastoma multiform (GBM) is the most common and lethal primary brain tumor found in adults. Despite the advances made in the field of cancer therapy in the last decade, the median survival rate remains less than a year. Therefore, a better understanding of the molecular biology of GBM will reveal the mechanisms responsible for the initiation and progression of the tumor, and allow the development of new therapeutic strategies. GBM contains a minority cell population, characterized by tumor initiating cells expressing the stem cell marker, CD133. The CD133+ GBM cells are responsible for tumor initiation, maintenance, progression and resistance to chemo/radiotherapy. The CD133+ cells represent a valuable and specific therapeutic target against GBM. The Polycomb (PcG) group family of transcriptional repressors have been involved in a vast range of cancers. The PcG protein and oncogene BMI1 is the best-characterized PcG protein. The implication of BMI1 in normal and cancer stem cell survival, self-renewal and maintenance has been thoroughly investigated. BMI1 is highly expressed in GBM and more precisely; it is enriched specifically in CD133+ cell populations. The main goal of this thesis was to elucidate the potential role of BMI1 in GBM CD133 + cancer stem cell (CSC) maintenance and radioresistance. The main function of BMI1 is to repress the expression of the genes encoded by the INK4A/ARF locus, which is implicated in the activation of two major tumor suppressor pathways, P53 and RB. However, BMI1 depletion in vitro induces a reduction in proliferation potential, as well as an increase in differentiation, apoptosis, and radiosensitivity regardless of INK4A/ARF status. Indeed, two-thirds of all tumors posses a deletion of this locus, suggesting that BMI1 regulates other targets. P21, a cell cycle regulator, was identified as a new BMI1 target. Moreover, we have observed that the loss of BMI1 inhibits the establishment of a cerebral tumor in a xenograft mouse model. In addition to transcription related activity, we identified a new transcription independent function of BMI1. After the induction of a DNA double-strand-break, BMI1 is rapidly recruited to the damage site and influences the recruitment of DNA damage response proteins. Furthermore, defects in DNA damage recognition and repair are observed after BMI1 knockdown. Consistent with these results, BMI1 overexpression induces DNA damage response and increases radioresistance potential. These results emphasize for the first time the requirement of BMI1 for the maintenance, self-renewal, and radioresistance in GBM CSC, thus providing a potential target for future therapeutic strategies against GBM.;Keywords: GBM, CSC, BMI1, self-renewal, DNA damage, radioresistance.
机译：胶质母细胞瘤（GBM）是成年人中最常见，最致命的原发性脑肿瘤。尽管在过去十年中癌症治疗领域取得了进步，但中位存活率仍不到一年。因此，对GBM分子生物学的更好理解将揭示导致肿瘤发生和发展的机制，并允许开发新的治疗策略。 GBM包含少数细胞群，其特征在于表达干细胞标记CD133的肿瘤起始细胞。 CD133 + GBM细胞负责肿瘤的发生，维持，进展以及对化学疗法/放射疗法的抵抗力。 CD133 +细胞代表了针对GBM的有价值的特异性治疗靶标。转录阻遏物的Polycomb（PcG）组家族已参与多种癌症。 PcG蛋白和致癌基因BMI1是最典型的PcG蛋白。 BMI1在正常和癌症干细胞存活，自我更新和维持中的意义已被彻底研究。 BMI1在GBM中得到了较高的表达，更确切地说是在BGM1中。它在CD133 +细胞群中特别富集。本文的主要目的是阐明BMI1在GBM CD133 +癌症干细胞（CSC）维持和放射抵抗中的潜在作用。 BMI1的主要功能是抑制INK4A / ARF基因座编码的基因的表达，这与两个主要的肿瘤抑制途径P53和RB的激活有关。但是，无论INK4A / ARF处于何种状态，体外BMI1的消耗都会导致增殖潜能的降低以及分化，凋亡和放射敏感性的增加。实际上，所有肿瘤的三分之二都具有该基因座的缺失，这表明BMI1调节着其他靶标。 P21，细胞周期调节剂，被确定为新的BMI1目标。此外，我们已经观察到BMI1的丢失会抑制异种移植小鼠模型中脑肿瘤的建立。除了转录相关的活动，我们确定了BMI1的新的转录独立功能。诱导DNA双链断裂后，BMI1迅速募集到损伤位点，并影响DNA损伤反应蛋白的募集。此外，BMI1敲低后观察到DNA损伤识别和修复的缺陷。与这些结果一致，BMI1的过表达诱导DNA损伤反应并增加抗辐射能力。这些结果首次强调了BMI1对GBM CSC的维持，自我更新和放射抗性的要求，从而为将来针对GBM的治疗策略提供了潜在的目标。关键词：GBM，CSC，BMI1，自我更新， DNA损伤，抗辐射。

著录项

  • 作者

    Facchino, Sabrina.;

  • 作者单位

    Universite de Montreal (Canada).;

  • 授予单位 Universite de Montreal (Canada).;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 258 p.
  • 总页数 258
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;
  • 关键词

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